DESCRIPTION: The proposed study builds upon the existing recruitment of study subjects and procurement of epidemiologic data and blood samples from two ongoing studies of lung cancer, led by Drs. Margaret Spitz and Waun Ki Hong. The application proposes to validate the findings of a preliminary case-control study which revealed that the level of in vitro benzo[a]pyrene diol epoxide (BPDE)-induced DNA adducts was significantly associated with the risk of lung cancer. The rationale for developing this biomarker is not given the same in-vitro exposure to smoking-related carcinogens, cells from some individuals did not remove carcinogen-induced adducts sufficiently, indicating an increased risk of developing smoking-related cancer. The study will evaluate the usefulness of this new in vitro-induced DNA adduct assay and identify individuals who may be susceptible to smoking-related cancers. Using the study protocol, personnel, and data-collection instruments currently in operation, the preliminary study of 21 cases and 41 controls to a case-control will be expanded to a study of 250 lung-cancer cases and 250 healthy controls (matched by age, sex ethnicity and smoking status). The application outlines the following Specific Aims: 1) to determine the association between the levels of in vitro-induced carcinogen adducts and risk of lung cancer; 2) to determine the correlation between levels of BPE-induced adducts and DNA repair capacity; and 3) to determine the association of the levels of BPE-induced DNA adducts with other related susceptibility factors and biomarkers for lung-cancer risk. The level of DNA adducts induced by in vitro by an ultimate carcinogen (BPDE) largely reflects the level of overall genomic repair capacity of the whole cells plus cellular detoxification. It is hypothesized that the in vitro-induced adducts associated with lung cancer susceptibility will substantiate the predictive role of this new BPDE-induced DNA adduct assay in identifying subgroups of smokers at particularly high risk for developing lung cancer and further elucidate the mechanisms of tobacco carcinogenesis. Such high-risk individuals would be targetted for intensive smoking cessation interventions, could be enrolled in chemoprevention trials and might be suitable for screening programs, not appropriate for the general population.